ZOOM: A prospective, randomized trial of zoledronic acid (ZOL; q 4 wk vs q 12 wk) for long-term treatment in patients with bone-metastatic breast cancer (BC) after 1 yr of standard ZOL treatment.

Abstract

9005 Background: ZOL (4 mg q 4 wk) is an established therapy for reducing the risk of debilitating skeletal-related events (SREs) in patients (pts) with bone metastases (mets) from BC. As BC treatments continue to improve pt survival, long-term SRE-reduction is increasingly important, and evaluation of modified ZOL dosing to retain efficacy with reduced adverse events (AEs) is warranted. Methods: ZOOM, a phase III prospective, randomized, open-label, multicenter study, assessed the safety and efficacy of quarterly (4 mg q 12 wk; Arm 1) vs monthly (4 mg q 4 wk; Arm 2) ZOL for ~1 yr in pts with BC who have ≥ 1 bone met, and have received ~1 yr of prior ZOL treatment (9 to 12 doses over ≤ 15 months; last dose ≤ 3 months prior). The primary endpoint was skeletal morbidity rate (SMR; number of SREs/pt/yr). Sample size to detect non-inferiority with 80% power (1-sided a = 0.025) was 420 pts. Secondary endpoints included time to first SRE, bone pain, bone marker (N-telopeptide of type I collagen; NTX) levels, and safety. Results: 425 pts were enrolled (209 in Arm 1; 216 in Arm 2); arms were well balanced for pt and disease characteristics, and anticancer therapies. SMR was similar between arms: 0.26 (95% confidence interval [CI] = 0.15, 0.37) in Arm 1 vs 0.22 (95% CI = 0.14, 0.29) in Arm 2; between-arms difference = 0.04 (upper limit of 1-tailed 97.5% CI = 0.17). Despite the proximity of 0.17 to the adjusted non-inferiority margin (0.19), the non-inferiority of Arm 1 vs 2 remains statistically significant. Safety analyses showed that ZOL was well tolerated. Renal AEs were reported in similar proportions of pts in both arms; 7 cases of osteonecrosis of the jaw were reported (1.65% overall; 4 cases in Arm 1 vs 3 in Arm 2). Conclusions: ZOOM is the first randomized trial to compare ZOL q 12 wk vs ZOL q 4 wk in BC pts after 1 yr of standard ZOL therapy. SMR was similar between arms. Limitations in study design suggest the need to confirm non-inferiority of ZOL q 12 wk in other ongoing phase III trials.

NCCN Task Force Report: Bone Health in Cancer Care

“…The randomized phase III ZOOM trial assessed the safety and efficacy of switching to quarterly zoledronic acid versus continuing with monthly in patients (n=425) with bone metastases from breast cancer who received prior zoledronic acid treatment. 264 Safety analyses showed that zoledronic acid was well tolerated in the long term, and renal adverse events were seen in similar proportions of patients in both arms. This study was underpowered to confirm noninferiority between the arms, although rates of SREs were similar.…”

“…This study was underpowered to confirm noninferiority between the arms, although rates of SREs were similar. 264 Similarly, the ongoing OPTIMIZE 2 trial is studying patients with breast cancer with bone metastases who have received prior monthly zoledronic acid. OPTIMIZE 2 patients are randomized in a double-blind fashion to continue monthly dosing for an additional year versus changing dosing intervals to every 3 months (ClinicalTrials.gov identifier: NCT00320710).…”

De-escalated administration of bone-targeted agents in patients with breast and prostate cancer—A survey of Canadian oncologists

“…There is considerable interest in optimizing the frequency of administration of bone-targeted agents as the current “one size fits all” approach is likely inefficient, expensive, and there is reason to believe that some patients may achieve equivalent benefit and improved safety with less frequent treatment administration. The results of the two published trials, assessing reduced frequencies of administration of these agents, would suggest there is still a need for larger definitive studies [12] , [13] . In addition, we are not aware of any similar studies planned for prostate cancer where again the benefits of bone-targeted agents in reducing SREs are likely even more modest than that seen in breast cancer patients.…”

“…The results do however confirm that physicians are very interested in de-escalation trials and that they would consider de-escalating therapy from every 3–4 weeks to 3 monthly therapy and entering patients on such a study at anytime from 3 months to 2 years after starting treatment. However, physicians do want the primary study endpoint to be SRE [11] and not biomarker studies using biomarkers of bone turnover as a surrogate for skeletal related event risk [12] . Ultimately the results from our survey confirms that trials exploring de-escalated use of bone targeted agents are wanted for both breast and prostate cancer and that ultimately there will remain a need for further very large randomised trials with skeletal related events as the primary endpoint.…”

“…To date, two trials have been presented assessing reduced frequencies of administration of these agents in metastatic breast cancer patients [12] , [13] and others are still on going [17] . Despite this, the results of the published trials would suggest that there is still a need for larger definitive studies.…”